The present invention provides novel methodologies for the preparation of unsaturated piperidines, such as 3,4-unsaturated 4-arylpiperidines, from piperidones through silyl reagents via the Shapiro reaction and palladium-catalyzed cross-coupling reactions with organo halides, such as aryl iodides and bromides. Embodiments of this invention provide synthetic methodologies for making benzyl-protected, 3,4-unsaturated piperidine, which contains an aryldialkylalkenylsilane moiety, such as a benzyldimethylalkenylsilane moiety, from 1-benzyl-4-piperidone via the Shapiro reaction. This silyl piperidine readily undergoes palladium-catalyzed cross-coupling reactions with a variety of organo halides, such as aryl iodides and bromides, to generate 3,4-unsaturated piperidines, such as 3,4-unsaturated 4-arylpiperidines. Many of these coupling reactions according to this invention proceed at ambient temperature. These reactions present useful methods for 3,4-unsaturated piperidine and 4-arylpiperidine syntheses.
The 4-arylpiperidine moiety is commonly employed as a structural unit in numerous drug discovery programs, including those with potential application to the treatment of asthma,1 hypertension,2 depression,3 migraine headaches,4 bacterial infections,5 prostrate gland enlargement,6 estrogen-related disorders,7 neurodegenerative disorders (e.g. Alzheimer's disease),8 neuronal excitotoxicity (e.g. epilepsy, Parkinson's disease),9 cocaine abuse,10 and allergic rhinitis.11 Both the 4-aryl group and the N-substituent are frequently used as points of structural diversification within such programs.1,3c,4a,5,9,11 
Because relatively few 4-arylpiperidines are commercially available, new synthetic routes to obtain such compounds are desirable. The most common methods that are currently applied include the condensation of a 4-piperidone derivative with an anionic aryl species (Scheme 1, Eq. (1)),3-4,8-12 the cross-coupling of a fully saturated piperidine reagent (Eq. (2)),13 and the cross-coupling of a 3,4-unsaturated piperidine reagent (Eq. (3)).1-2,5-7,14 The first of these three methods is often undesirable due to its harsh reaction conditions (i.e., strong nucleophiles and acids). The latter two methods are thus advantageous because they generally involve milder reaction conditions.

One disadvantage, however, that exists for the cross-coupling methods represented in Equations (2) and (3) is that the requisite piperidine reagents are generally not carried through multiple synthetic steps. They instead undergo the cross-coupling reaction immediately following their synthesis. Thus the manner in which a 4-arylpiperidine unit can be diversified within a drug discovery program is limited. This situation exists primarily because tin reagents introduce issues of toxicity and difficult by-product removal, while triflate, zinc, and boron reagents introduce issues of reagent instability and incompatibility.
Organosilanes have recently emerged as alternative cross-coupling reagents that possess the advantages of low toxicity and high stability.15 Benzyldimethylsilyl reagents in particular exhibit notable stability toward acids and bases,16 and they can be carried through multiple synthetic steps.17 It was ascertained in the context of this invention whether a 3,4-unsaturated piperidine reagent containing a benzyldimethylsilyl moiety could be readily synthesized and successfully employed in the cross-coupling reaction represented in Equation (3). Some embodiments of this invention provide the application of the Shapiro reaction to efficiently convert 1-benzyl-4-piperidone into a benzyldimethylsilyl reagent. Other embodiments of this invention provide the use of palladium-catalyzed cross-coupling chemistry to subsequently transform this reagent into a variety of 3,4-unsaturated 4-arylpiperidines. Still other embodiments of this invention provide the application of the Shapiro reaction to efficiently convert 1-benzyl-4-piperidone into a benzyldimethylsilyl reagent and the use of palladium-catalyzed cross-coupling chemistry to subsequently transform this reagent into a variety of 3,4-unsaturated 4-arylpiperidines.